All Genetic Epidemiology Branch investigations evaluate the contributions of host susceptibility and environmental exposure in the development of cancer. In family studies, a second gene for melanoma on 12q, CDK4, was identified. Germline mutations were identified in 11/11 melanoma cases from two unrelated melanoma families. Linkage analyses that simultaneously examined markers from 9p and markers from 1p suggested that a 1p locus contributed to both melanoma and the combined trait CMM/DN, whereas a 9p locus contributed more to CMM alone. A candidate gene for nevoid basal cell carcinoma syndrome on 9q, PTC, was identified. PTC is the human homolog of the Drosophila segment polarity gene patched. Mutations were identified in NBCC patients as well as in tumors associated with the syndrome. The gene for Cowden's disease was mapped to a small region of chromosome 10q. Examination of 12 families from 4 countries, in an international collaboration, showed no evidence of heterogeneity. We identified 20 different germline NF2 mutations in 21 unrelated families. Patients with nonsense and frameshift mutations were younger at onset and had a higher frequency and mean number of tumors than patients with splice site mutations, supporting a correlation between nonsense and frameshift mutations and severe NF2. Retinal abnormalities were detected only in nine patients from five families with nonsense mutations: this may represent a new genotype-phenotype correlation.